Hydrogenated nitrogen containing tetracycles having two nonadjacent lactam rings

ABSTRACT

Novel hydrogenated heterocyclic compounds, containing two nitrogen atoms, of the formula ##STR1## in which R 1 , R 2 , R 3 , R 5  and R 7  are each, independently of the others, hydrogen or lower alkyl, m is 2 or 3, n is 1 or 2, and either R 4  and R 6  are each hydrogen or R 4  and R 6  together form an additional bond, in free form or in form of a salt, can be used as pharmaceutical active ingredients for memory improvement and can be manufactured in a manner known per se.

The invention relates to hydrogenated heterocyclic compounds, containingtwo nitrogen atoms, of the formula ##STR2## in which R₁, R₂, R₃, R₅ andR₇ are each, independently of the others, hydrogen or lower alkyl, m is2 or 3, n is 1 or 2, and either R₄ and R₆ are each hydrogen or R₄ and R₆together form an additional bond, in free form or in form of a salt, tothe use of these compounds, to a process for the manufacture of thesecompounds and to pharmaceutical compositions containing such a compoundI in free form or in the form of a pharmaceutically acceptable salt.

Within the scope of the invention, the compounds I may be in the form ofstereoisomers. Since the compounds I contain at least three chiralcarbon atoms (C-atoms) (that is the C-atoms that are involved in linkingthe four (theoretical) isolated basic ring structures to the tetracylicstructure shown in formula I), they may be, for example, in the form ofpure enantiomers, mixtures of enantiomers, such as racemates, purediastereoisomers, mixtures of diastereoisomers or mixtures of racemates.Within the scope of the invention preferred compounds I are thosehaving, at the three above-mentioned chiral C-atoms, the sterochemistrydisclosed by way of example.

Compounds I in salt form are especially corresponding acid additionsalts, preferably pharmaceutically acceptable acid addition salts. Theseare formed, for example, with strong inorganic acids, such as mineralacids, for example sulfuric acid, a phosphoricacid or a hydrohalic acid,with strong organic carboxylic acids, such as lower alkanecarboxylicacids, for example acetic acid, saturated or unsaturated dicarboxylicacids, for example malonic, maleic or fumaric acid, or hydroxycarboxylicacids, for example tartaric or citric acid, or with sulfonic acids, suchas lower alkanesulfonic acids or unsubstituted or substitutedbenzenesulfonic acids, for example methane- or p-toluene-sulfonic acid.Also includes are salts that are suitable for pharmaceutical uses, sincethese can be used, for example, for the isolation or purification offree compounds I and their pharmaceutically acceptable salts.

Throughout this specification, radicals or compounds designated "lower"are to be understood as those having up to and including 7, especiallyup to and including 4, carbon atoms, unless otherwise specified.

Lower alkyl is C₁ -C₄ alkyl, i.e., methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec.-butyl or tert.-butyl and also includes C₅ -C₇alkyl radicals, i.e. corresponding pentyl, hexyl or heptyl radicals.

Halogen is halogen having an atomic number of up to and including 53,i.e. chlorine or bromine, or also fluorine or iodine.

The compounds I possess, for example, valuable pharmacological,especially nootropic, properties.

In, for example, the Two-Compartment Passive Avoidance test model[according to Mondadori and Classen, Acta Neurol. Scand. 69, Suppl. 99,125 (1984)], they cause a distinct reduction in the amnesic effect of acerebral electric shock in mice at dosages of approximately 0.3 mg/kgand above i.p. and p.o.

The compounds I also have a considerable memory-improving action, whichcan be observed in the Step-down Passive Avoidance Test [according toMondadori and Waser, Psychopharmacol. 63, 297 (1979)] in mice at adosage of approximately 0.3 mg/kg and above p.o.

Furthermore, the compounds I have a significant memory-refreshingactivity, which can be demonstrated by way of the Step-through DarkAvoidance Test model in mice at a dosage of approximately 0.3 mg/kg andabove p.o.

Accordingly, the compounds I, in free form or in form of apharmaceutically acceptable salt, can be used, for example, as activeingredients in nootropics that are used, for example, for the treatmentof cerebral deficiency phenomena, especially memory disorders. Theinvention thus relates to the use of compounds I, in free form or inform of a pharmaceutically acceptable salt, for the manufacture ofcorresponding medicaments. The commercial preparation of the activeingredients is also included.

Preferred within the scope of the invention are compounds of the formulaI, in which R₁, R₂, R₃, R₅ and R₇ are each, independently of the others,hydrogen or lower alkyl, m is 2 or 3, n is 1 or 2, and R₄ and R₆ areeach hydrogen, in free form or in form of a salt.

Especially preferred within the scope of the invention are compounds ofthe formula I, in which R₁, R₂, R₃, R₅ and R₇ are each, independently ofthe others, hydrogen or lower alkyl, m is 2, n is 1, and either R₄ andR₆ are each hydrogen or R₄ and R₆ together form an additional bond, infree form or in form of a salt.

Especially preferred within the scope of the invention are compounds ofthe formula I, in which R₁, R₂, R₃, R₅ and R₇ are each, independently ofthe others, hydrogen or lower alkyl, m is 2, n is 1, and R₄ and R₆ areeach hydrogen, in free from or in form of a salt.

Especially preferred within the scope of the invention are compounds ofthe formula I, in which R₁, R₂, R₃, R₅ and R₇ are each hydrogen, m is 2,n is 1, and either R₄ and R₆ are each hydrogen or R₄ and R₆ togetherform an additional bond, in free form or in form of a salt.

Most preferred within the scope of the invention are compounds of theformula I, in which R₁, R₂, R₃, R₅ and R₇ are each hydrogen, m is 2, nis 1, and R₄ and R₆ are each hydrogen, in free form or in form of asalt.

Specifically preferred within the scope of the invention are thecompounds of the formula I mentioned in the Examples, in free form or inthe form of a salt.

The present invention also relates to a process for the manufacture ofcompounds of the formula I, which process comprises, for example,

a) for the manufacture of compounds I, in which R₄ and R₆ together forman additional bond, oxidising a compound of the formula ##STR3## or asalt thereof or

b) for the manufacture of compounds I, in which R₄ and R₆ are eachhydrogen, in a compound of the formula ##STR4## in which either X₁ andX₂ together are an additional bond and X₃ is hydrogen, or X₁ is hydrogenand X₂ and X₃ together are an additional bond, or in a salt thereof,reducing to a single bond the double bond between the carbon atomscarrying the radicals X₁ and X₂ or between the carbon atoms carrying theradicals X₂ and X₃ and, if desired, in each case separating a mixture ofisomers obtainable in accordance with the process into its componentsand/or converting a free compound I obtainable in accordance with theprocess into a salt or conveying a salt obtainable in accordance withthe process into the free compound I or into a different salt.

The reactions described hereinbefore and hereinafter are carried out ina manner known pre se, for example in the absence or usually in thepresence of a suitable solvent or diluent or a mixture thereof, thereactions being carried out, as required, with cooling, at roomtemperature or with heating, for example in a temperature range ofapproximately from -80° C. to the boiling temperature of the reactionmedium, preferably from approximately -20° C. to approximately 150° C.and, if necessary, in a closed vessel, under pressure, in an inert gasatmosphere and/or under anhydrous conditions.

The starting material mentioned hereinbefore and hereinafter are usedfor the manufacture of compounds I are known or can be manufacturedaccording to methods known per se, for example in accordance with theprocedures described hereinafter.

The information given hereinbefore regarding the salts of compounds Iapplies in an analogous manner also to the salts of the startingmaterials.

The oxidation according to process variant a) can be carried out byvarious methods.

For example, compounds II or salts thereof can be oxidised by reactionwith a peroxo compound, for example with hydrogen peroxide or a saltthereof, such as sodium peroxide, peroxodisulfuric acid or a saltthereof, such sodium peroxodisulfate, or an organic peracid, such asperformic acid, peracetic acid or an unsubstituted or substituted, forexample halogenated, perbenzoic acid, such as perbenzoic acid orm-chloroperbenzoic acid, in the presence of a solvolysis agent, forexample water, an alcohol, for example a lower alkanol, such as ethanol,or an acid, for example an organic carboxylic acid, such as anunsubstituted or halogenated lower alkanecarboxylic acid, such as formicacid, acetic acid or trifluoroacetic acid. Depending on the oxidationconditions, α,β-unsaturated lactams, β,γ-unsaturated lactams or mixturesof the two types of lactam (which can generally be separated into thecomponents in customary manner, for example by chromatography) can beobtained in this oxidation process. Suitable oxidation conditions forthe formation of the desired α,β-unsaturated lactams are the conditionscustomarily applied for such oxidations and are advantageously thosespecified in the Examples, the desired α,β-unsaturated lactam beingisolated from the mixture of the two mentioned types of lactam in thecase that such a mixture is obtained.

It is, however, also possible for compounds II or salts thereof first ofall to be converted with a suitable halogenating agent, such as anN-halosuccinimide, for example N-bromosuccinimide orN-chlorosuccinimide, into the halogenated compounds of formula ##STR5##in which Hal is halogen, preferably chlorine or especially bromine, orsalts thereof, and for these then to be solvolysed in a second step tocompounds I, in which R₄ and R₆ together form and additional bond, forexample by means of one of the afore-mentioned solvolysis agents, ifappropriate in the presence of suitable catalysts, such as heavy metalcatalysts, for example platinum catalysts, such astetrakis(triphenylphosphane)palladium(O). Suitable halogenation andsolvolysis conditions are the conditions customarily applied for suchreactions and are advantageously those specified in the Examples.

Compounds of formula II and salts thereof are known or can bemanufactured analogously to known materials.

Depending on the position of the double bond to be reduced, the startingmaterials III for the process variant b) can be used either in the formof α,β-unsaturated lactams (X₁ +X₂ =bond; X₃ =hydrogen) or in the formof β,γ-unsaturated lactams (X₁ =hydrogen; X₂ +X₃ =bond) or in the formof mixtures of α,β-unsaturated and β,γ-unsaturated lactams. Theα,β-unsaturated lactams are identical with the compounds I obtainableaccording to process variant a), in which R₄ and R₆ together form anadditional bond.

The reduction of the carbon-carbon double bond to a single bond in theunsaturated lactams III is carried out in customary manner by treatmentwith a suitable reducing agent, for example by hydrogenation in thepresence of a hydrogenation catalyst, by reduction with ahydride-transferring reagent or by reduction with a metal reductionsystem comprising a metal and a proton-removing agent.

Suitable hydrogenation catalysts are, for example, elements of sub-groupVIII of the Periodic Table of Elements or derivatives thereof, such aspalladium, platinum, platinum oxide, ruthenium, rhodium,tris(triphenylphosphane)rhodium(I)halide, for exampletris(triphenylphosphane)rhodium(I) chloride, or Raney nickel, which areoptionally applied to a carrier, such as activated carbon, an alkalimetal carbonate or sulfate or a silica gel. There come intoconsideration as hydride-transferring reagents, for example, suitablelight metal hydrides, especially alkali metal aluminum hydrides andborohydrides, such as lithium aluminium hydride, lithiumtriethylborohydride, sodium borohydride, sodium cyanoborohydride or tinhydrides, such as triethyltin or tributyltin hydride, or diborane. Themetal component of a metal reduction system is, for example, a basemetal, such as an alkali metal or alkaline earth metal, for examplelithium, sodium, potassium, magnesium or calcium, or a transition metal,for example zinc, tin, iron or titanium, and there come intoconsideration as proton-removing agents, for example, protonic acids ofthe kind mentioned hereinbefore in the definition of acid additionsalts, such as hydrochloric or acetic acid, lower alkanols, such asethanol, and/or amines or ammonia. Examples of such systems aresodium/ammonia, zinc/hydrochloric or acetic acid, or zinc/ethanol.

The reduction of compounds III and salts thereof is carried out, forexample, in the presence of a suitable inert solvent or diluent, such asan unsubstituted or halogenated hydrocarbon, for example hexane,cyclohexane, benzene, toluene, dichloromethane or chlorobenzene, anether, for example diethyl ether, dioxan or tetrahydrofuran, or aketone, for example acetone or 2-butanone, and at room temperature orwith gentle heating, for example in a temperature range of fromapproximately 20° to approximately 100° C.

Especially preferred forms of the reduction process are illustrated inthe Examples.

The manufacture of the starting materials III and their salts is carriedout in customary manner, for example by oxidation of compounds II orsalts thereof, the oxidation being carried out in a manner analogous tothat described under process variant a) and the oxidation conditions ineach case being selected in such a way that the desired type(s) of thepossible types of lactam is(are) obtained. Suitable oxidation conditionsare the conditions customarily applied for such oxidations and areadvantageously those specified in the Examples.

Salts of compounds I can be produced in a manner known per se. Forexample acid addition salts of compounds I are obtained by treatmentwith a suitable acid or a suitable ion exchange reagent. Salts ofcompounds I can be converted in customary manner into free compounds I;acid addition salts can be converted, for example, by treatment with asuitable basic agent or a suitable ion exchange reagent.

Salts of compounds I can be converted into different salts of compoundsI in a manner known per se. Acid addition salts, for example, can beconverted into different acid addition salts, for example by treating asalt of an inorganic acid, such as a hydrochloride, with a suitablemetal salt, such as a sodium, barium or silver salt, of an acid, forexample with silver acetate, in a suitable solvent in which theinorganic salt that is forming, for example silver chloride, isinsoluble and thus separates out of the reaction mixture.

Depending on the procedure and on the reaction conditions compounds Ihaving salt-forming properties are obtained in free form or in the formof salts.

Owing to the close relationship between the compound I in free form andin the form of its salts, throughout this specification references tothe free compound I or its salts shall, where appropriate, also includethe corresponding salts or the free compound I, respectively.

Compounds I, including their salts of salt-forming compounds, can alsobe obtained in the form of their hydrates and/or may contain othersolvents that have been used, for example, for the crystallisation ofcompounds that exist in solid form.

The compounds I and their salts may be in the form of one of thepossible isomers or in the form of a mixture, depending on the startingmaterials and procedures chosen. Depending on the symmetry of themolecule, for example depending on the number and the absolute andrelative configuration of the centres of chirality, such as asymmetricC-atoms, there are obtainable as pure isomers, for example, pureenantiomers and/or pure diastereoisomers, such as pure cis/trans-isomersor meso compounds. Similarly, mixtures of isomers may be, for example,mixtures of enantiomers, such as racemates, mixtures of diastereoisomersor mixtures of racemates. Mixtures of isomers of compounds I in freeform or in salt form that are obtainable in accordance with the processor by some other method can be separated into the components incustomary manner.

Resulting mixtures of diastereoisomers and mixtures of racemates can beseparated into the pure diastereoisomers or racemates in known manner onthe basis of the physical-chemical differences between the constituents,for example by fractional crystallisation, distillation and/orchromatography.

Resulting mixtures of enantiomers, such as racemates, can be separatedinto the enantiomers according to known methods, for example byrecrystallisation from an optically active solvent, chromatography onchiral adsorbents, with the aid of suitable microorganisms, by cleavingwith specific immobilised enzymes, by the formation of inclusioncompounds, for example using chiral crown ethers, in which only oneenantiomer is complexed, or by conversion into diastereoisomeric salts,for example by reaction of a basic end product racemate with anoptically active acid, such as carboxylic acid, for example tartaric ormalic acid, or a sulfonic acid, for example camphorsulfonic acid, andseparation of the mixtures of diastereoisomers obtained in this manner,for example on the basis of their different solubilities, into thediastereoisomers from which the desired enantiomer can be freed by theaction of suitable agents. Advantageously the more active enantiomer isisolated.

The invention relates also to those forms of the process according towhich a compound obtainable as intermediate at any stage of the processis used as starting material and the remaining steps are carried out, ora starting material is used in the form of a derivative or salt and/orits racemates or enantiomers or, especially, is formed under thereaction conditions.

The starting materials and intermediates used in the process accordingto the present invention, each in free form or salt form, are preferablythose that result in the compounds I described at the beginning as beingespecially valuable.

The invention also relates to novel materials and intermediates, in eachcase in free form or in salt form, for the manufacture of the compoundsI, to the use thereof and to processes for their manufacture, thevariables R₁, R₂, R₃, R₄, R₅, R₆, R₇, m and n having the meanings givenfor compounds I.

The invention relates also to the use of compounds I and theirpharmaceutically acceptable salts for the treatment of cerebraldeficiency phenomena, especially memory disorders, preferably in theform of pharmaceutically acceptable preparations, especially in a methodfor the therapeutic treatment of the animal or human body, and to such amethod of treatment.

The invention relates equally to pharmaceutical preparations hat containa compound I or a pharmaceutically acceptable salt thereof as activeingredient, and to processes for the manufacture thereof. Thesepharmaceutical preparations are for enteral, such as oral, and alsorectal or parenteral administration to warm-blooded animals, and containthe pharmacologically active ingredient on its own or together withconventional pharmaceutical adjuncts. The pharmaceutical preparationscontain, for example, approximately from 0.1% to 100%, preferably fromapproximately 1% to approximately 50%, active ingredient. Pharmaceuticalpreparations for enteral and parenteral administration are, for example,those in dosage unit forms, such as drages, tablets, capsules orsuppositories and also ampoules. They are prepared in a manner known perse, for example by means of conventional mixing, granulating,confectioning, dissolving or lyophilising processes. For example,pharmaceutical preparations for oral administration can be obtained bycombining the active ingredient with solid carriers, where appropriategranulating a resulting mixture, and processing the mixture orgranulate, if desired or necessary after the addition of suitableadjuncts, into tablets or drage cores.

Suitable carriers are especially fillers, such as sugers, for examplelactose, saccharose, mannitol or sorbitol, cellulose preparations and/orcalcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate, and also binders, such as starch pastes, using, for example,corn, wheat, rice or potato starch, gelatin, tragacanth, methylcelluloseand/or polyvinylpyrrolidone and, if desired, disintegrators, such as theabove-mentioned starches, also carboxymethyl starch, crosslinkedpolyvinylpyrrolidone, agar or alginic acid or a salt thereof, such assodium alginate. Adjuncts are especially flow-regulating agents andlubricants, for example silicic acid, talc, stearic acid or saltsthereof, such as magnesium or calcium stearate, and/or polyethyleneglycol. Drage cores are provided with suitable coatings that may beresistant to gastric juices, there being used, inter alia, concentratedsugar solutions that optionally contain gum arabic, talc,polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, orlacquer solutions in suitable organic solvents or solvent mixtures or,to produce coatings that are resistant to gastric juices, solutions ofsuitable cellulose preparations, such as acetylcellulose phthalate orhydroxypropylmethylcellulose phthalate. Colouring substances or pigmentsmay be added to the tablets or drage coatings, for example for thepurpose of identification or to indicate different doses of activeingredient.

Other orally administrable pharmaceutical preparations are dry-filledcapsules made of gelatin, and also soft, sealed capsules made of gelatinand a plasticiser, such as glycerol or sorbitol. The dry-filled capsulesmay contain the active ingredient in the form of a granulate, forexample in admixture with fillers, such as lactose, binders, such asstarches, and/or glidants, such as talc or magnesium stearate, and,where appropriate, stabilisers. In soft capsules the active ingredientis preferably dissolved or suspended in suitable liquids, such as fattyoils, paraffin oil or liquid polyethylene glycols, it being possiblealso for stabilisers to be added.

Suitable rectally administrable pharmaceutical preparations are, forexample, suppositories that consist of a combination of the activeingredient with a suppository base material. Suitable suppository basematerials are, for example, natural or synthetic triglycerides, paraffinhydrocarbons, polyethylene glycols or higher alkanols. It is alsopossible to use gelatin rectal capsules that contain a combination ofthe active ingredient with a base material. Suitable base materials are,for example, liquid triglycerides, polyethylene glycols or paraffinhydrocarbons.

There are suitable for parenteral administration especially aqueoussolutions of an active ingredient in water-soluble form, for example inthe form of a water-soluble salt, and also suspensions of the activeingredient, such as corresponding oily injection suspensions, for whichsuitable lipophilic solvents or vehicles, such as fatty oils, forexample sesame oil, or synthetic fatty acid esters, for example ethyloleate or triglycerides, are used, or aqueous injection suspensions thatcontain viscosity-increasing substances, for example sodiumcarboxymethylcellulose, sorbitol and/or dextran, and, where appropriate,also stabilisers.

The dosage of the active ingredient may depend on various factors, suchas mode of administration, warm-blooded species, age and/or individualcondition. For oral administration, the approximate daily dosagenormally to be recommended for a warm-blooded animal weighingapproximately 75 kg is from approximately 20 mg to approximately 1500mg, especially from approximately 50 to approximately 250 mg, which isadvantageously taken in several equal partial doses.

The following Examples illustrate the above-described invention but arenot intended to limit the scope thereof in any way. Temperatures aregiven in degrees Celsius.

EXAMPLE 1

a) 700 mg (2.8 mmol) of(9aR*,9bR*,13aR*)-2,7-dioxo-1,4,5,7,9a,10,11,12,13,13a-decahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole,dissolved in 30 ml of tetrahydr are hydrogenated with hydrogen in thepresence of 70 mg of PtO₂ at room temperature under normal pressureuntil the absorption of hydrogen ceases. The catalyst is filtered offand the filtrate is concentrated by evaporation in vacuo. The resultingoil is crystallised from ethyl acetate. In this manner(9aR*,9bR*,13aR*)-2,7-dioxo-1,4,5,7,8,9,9a,10,11,12,13,13a-dodecahydro-2H-pyrrolo[2',1':3,4]pyrazino2,1-i]indoleof formula ##STR6## is obtained, that is to say the compound of formulaI in which R₁, R₂, R₃, R₄, R₅, R₆ and R₇ are each a hydrogen atom, m is2, n is 1 and the chiral C-atoms 9a, 9b and 13a have the above relativeconfiguration (each R*) (melting range: 135° to 136°). The mother liquoris concentrated by evaporation in vacuo and chromatographed on silicagel (0.040-0.063 mm) with trichloromethane and trichloromethane/methanol(99:1) as eluants. There is thus obtained(9aR*,9bS*,13aS*)-2,7-dioxo-1,4,5,7,8,9,9a,10,11,12,13,13a-dodecahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole,which is stereoisomeric as regards the relative configuration of the 9aC-atom, in the form of an oil which is crystallised from ethyl acetateand then melts at 177°-179°.

b) The α,β-unsaturated lactam used as starting material can bemanufactured, for example, as follows:

4.05 g (20 mmol) of m-chloroperbenzoic acid are added in portions atroom temperature, with stirring, to a solution of 2.3 g (10 mmol) of(9bR*,13aR*)-2-oxo-1,4,5,10,11,12,13,13a-octahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indolein 50 ml of dichloromethane (the exothermic reaction is maintained atroom temperature using an ice-bath). 2.28 g (20 mmol) of trifluoroaceticacid are then added dropwise to the reaction mixture which is thenstirred for 16 hours at room temperature. The reaction mixture isdiluted with 100 ml of dichloromethane and then washed in successionwith sodium hydrogen sulfite solution (5%) and sodium hydrogen carbonatesolution (5%). The organic phase is separated off, dried over sodiumsulfate and concentrated by evaporation in vacuo. The crude productobtainable in that manner is chromatographed on 210 g of silica gel(0.040-0.063 mm) using trichloromethane as eluant. In this manner(9aR*,9bR*,13aR*)-2,7-dioxo-1,4,5,7,9a,10,11,12,13,13a-decahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole is obtained in the form of an oil, which iscrystallised from dichloromethane/diethyl ether and melts at 159°-162°.

c) The α,β-unsaturated lactam used as starting material can also bemanufactured, for example, as follows:

2.3 g (10 mmol) of(9bR*,13aR*)-2-oxo-1,4,5,10,11,12,13,13a-octahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indoleare dissolved in 60 ml of absolute tetrahydrofuran. 1.78 g (10 mmol) ofN-bromosuccinimide are added in portions, at 0°, to the solution. Thereaction mixture is then stirred for 30 minutes at 0° and subsequentlyleft to stand at room temperature for 12 hours. The reddish mixture issubstantially concentrated in vacuo, 100 ml of diethyl ether and 100 mlof water are added to the residue, the mixture is extracted by shakingand the organic phase is separated off, washed in succession with 30 mlof 0.5M sodium hydrogen sulfite solution and 1N sodium hydrogencarbonate solution, dried over magnesium sulfate and freed of solvent.The residue is crystallised twice from diethyl ether/pentane. In thismanner a mixture consisting of 87%(9bR*,13bR*)7-bromo-2-oxo-1,4,5,10,11,12,13,13a-octahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole and 13%(9bR*,13aR*)-7,8-dibromo-2-oxo-1,4,5,10,11,12,13,13a-octahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole(melting range of the mixture: 118°-120°) is obtained, which is furtherused without additional purification.

0.618 g (2 mmol) of this bromide mixture and 0.820 g (10 mmol) ofanhydrous sodium acetate are dissolved at room temperature in 40 ml ofglacial acetic acid. 0.28 g (0.24 mmol) oftetrakis(triphenylphosphane)palladium(O) is added to the solution underargon. The reaction mixture is stirred for 6 hours at 100°, then cooledand freed of solvent in vacuo. The residue is taken up indichloromethane and the undissolved portions are filtered off overcelite. The filtrate is washed with 1N sodium hydrogen carbonatesolution and dried over magnesium sulfate. After removal of the solvent,a viscous red oil remains from which the pure(9aR*,9bR*,13aR*)-2,7-dioxo-1,4,5,7,9a,10,11,12,13,13a-decahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indolecan be separated by preparative thin layer chromatography [silica gel;eluant: toluene/ethanol/concentrated ammonia (90:20:1)] which, afterrecrystallisation from ethyl acetate/diethyl ether/pentane, melts at160°-162°.

EXAMPLE 2

985 mg (4 mmol) of(9bR*,13aR*)-2,7-dioxo-1,4,5,7,8,10,11,12,13,13a-decahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole,dissolved in 40 ml of tetrahydrofuran, are hydrogenated with hydrogen inthe presence of 98 mg of PtO₂ at room temperature under normal pressureuntil the absorption of hydrogen ceases. The catalyst is filtered offand the filtrated is concentrated by evaporation in vacuo. The resultingoily crude product is crystallised from ethyl acetate. In this manner(9aR*,9bR*,13aR*)-2,7-dioxo-1,4,5,7,8,9,9a,10,11,12,13,13a-dodecahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]-indoleis obtained which melts at 135° to 136°. The mother liquor isconcentrated by evaporation in vacuo and chromatographed on silica gel(0.040-0.063 mm) with trichloromethane and trichloromethane/methanol(99:1) as eluants. There is thus obtained(9aR*,9bS*,13aS*)-2,7-dioxo-1,4,5,7,8,9,9a,10,11,12,13,13a-dodecahydro-2H-pryrrolo[2',1':3,4]pyrazino[2,1-i]indole,which is stereoisomeric as regards the relative configuration of the 9aC-atom, in the form of an oil which is crystallised from ethyl acetateand then melts at 177°-179°.

The β,γ-unsaturated lactam used as starting material can bemanufactured, for example, as follows:

A solution of 3.04 g (15 mmol) of m-chloroperbenzoic acid in 30 ml ofdichloromethane is added dropwise over a period of 45 minutes, at -15°with stirring, to a solution of 2.3 g (10 mmol) of(9bR*,13aR*)-2-oxo-1,4,5,10,11,12,13,13a-octahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indolein 30 ml of dichloromethane. The reaction mixture is then stirred for 4hours at -15°, then diluted with 100 ml of dichloromethane and washed insuccession, ice-cold, with sodium hydrogen sulfite solution (5%) andsodium hydrogen carbonate solution (5%). The organic phase is separatedoff, dried over sodium sulfate and concentrated by evaporation in vacuo.In this manner a crude product is obtained, which is chromatographed on120 g of silica gel (0.040-0.063 mm) using trichloromethane as eluant.The desired(9bR*,13aR*)-2,7-dioxo-1,4,5,7,8,10,11,12,13,13a-decahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indoleis obtained from the appropriate fractions in the form of a foam, whichis crystallised from dichloromethane/diethyl ether and then melts at105° to 125°. Also obtained is the (9aR*,9bR*, 13aR*) isomer of2,7-dioxo-1,4,5,7,9a,10,11,12,13,13a-decahydro-2H-pryrrolo[2',1':3,4]pyrazino[2,1-i]indolein the form of an oil, which is crystallised fromdichloromethane/diethyl ether and then melts at 159° to 162°.

EXAMPLE 3

A solution of 3.04 g (15 mmol) of m-chloroperbenzoic acid in 30 ml ofdichloromethane is added dropwise over a period of 45 minutes at -15°,with stirring, to a solution of 2.3 g (10 mmol) of(+)-(9bR*,13aR*)-2oxo-1,4,5,10,11,12,13,13a-octahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indolein 30 ml of dichloromethane. The reaction mixture is then stirred for 4hours at -15°, then diluted with 100 ml of dichloromethane and washed insuccession, while ice-cold, with sodium hydrogen sulfite solution (5%)and sodium hydrogen carbonate solution (5%). The organic phase isseparated off, dried over sodium sulfate and concentrated by evaporationin vacuo. The(+)-(9bR*,13aR*)-2,7-dioxo-1,4,5,7,8,10,11,12,13,13a-decahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole is obtained in the form of a foam, which can befurther reacted without being further purified.

The(-)-(9bR*,13aR*)-2,7-dioxo-1,4,5,7,8,10,11,12,13,13a-decahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indoleis produced in an analogous manner, starting from 2.3 g (10 mmol) of(-)-(9bR*,13aR*)-2-oxo-1,4,5,10,11,12,13,13a-octahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole,and is obtained in the form of a foam, which can be further reactedwithout being further purified.

The starting materials can be manufactured, for example, as follows:

11.0 g of(±)-(9bR*,13aR*)-2-oxo-1,4,5,10,11,12,13,13a-octahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indoleare chromatographed in 22 portions each of 0.5 g on a Buchi glass column(600×50 mm) with tribenzoylcellulose as filler at about 7 bar withhexane/isopropanol (9:1) as eluant [detection: UV (230 nm)].Concentration by evaporation of the top fractions yields the crude(+)-enantiomer in the form of an oil, which crystallises from diethylether/petroleum ether. Recrystallisation from diethyl ether/petroleumether yields the pure(+)-(9bR*,13aR*)-2-oxo-1,4,5,10,11,12,13,13a-octahydro-2H-pryrrolo[2',1':3,4]pyrazino[2,1-i]indole,which melts at 122°-123° {[α]_(D) ²⁰ =+153.7°±1.0° (CHCl₃ ; c=1)}. Afterremoval of the mixed fractions the (-)-enantiomer is finally eluted.Concentration of the final fractions by evaporation yields the crude(-)enantiomer in the form of an oil, which crystallises from diethylether/petroleum ether. Recrystallisation from diethyl ether/petroleumether yields the pure(-)-(9bR*,13aR*)-2-oxo-1,4,5,10,11,12,13,13a-octahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole,which melts at 122°-123° {[α]_(D) ²⁰ =-154.8°±1.0° (CHCl₃ ; c=1)}.

EXAMPLE 4

2.21 g (9 mmol) of(+)-(9bR*,13aR*)-2,7dioxo-1,4,5,7,8,10,11,12,13,13a-decahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole,dissolved in 100 ml of tetrahydrofuran, are hydrogenated with hydrogenin the presence of 220 mg of PtO₂ at room temperature under normalpressure until the absorption of hydrogen ceases. The catalyst isfiltered off and the filtrate is concentrated in vacuo. The oily residueis dissolve in dichloromethane and the solution is then washed insuccession with 0.1N hydrochloric acid and sodium hydrogen carbonatesolution (5%). The organic phase is dried over sodium sulfate andconcentrated by evaporation in vacuo. In this manner a crude product isobtained which chromatographed on 60 g of silica gel (0.040-0.063 mm)using dichloromethane and dichloromethane/methanol (99:1) as eluants.The desired product is obtained in crude form (oil) from the appropriatefractions. The oil is dissolved in 50 ml of water and the solution isextracted twice with 50 ml of diethyl ether in each case. The aqueousphase is treated with decolorising carbon at room temperature and thenconcentrated by evaporation in vacuo. The residue is dried for 36 hoursunder a high vacuum. The pure(+)-(9aR*,9bR*,13aR*)-2,7-dioxo-1,4,5,7,8,9,9a,10,11,12,13,13a-dodecahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indoleis thus obtained in the form of a colourless oil, which contains 0.64equivalents of water {[α]_(D) ²⁰ =+53.7°±1.0° (CHCl₃ ;c=1)}.

The(-)-(9aR*,9bR*,13aR*)-2,7-dioxo-1,4,5,7,8,9,9a,10,11,12,13,13a-dodecahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indoleis produced in an analogous manner, starting from 1.97 g (8 mmol) of(-)-(9bR*,13aR*)-2,7-dioxo-1,4,5,7,8,10,11,12,13,13-a-decahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole,and is obtained in the form of a colourless oil, which contains 0.61equivalents of water {[α]_(D) ²⁰ =-52.1°±1.0° (CHCl₃ ; c=1)}.

EXAMPLE 5

Tablets, each containing 25 mg of the active ingredient, for example(9aR*,9bR*,13aR*)-2,7-dioxo-1,4,5,7,8,9,9a,10,11,12,13,13a-dodecahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole,can be prepared as follows:

    ______________________________________                                        Constituents (for 1000 tablets):                                              ______________________________________                                        active ingredient        25.0 g                                               lactose                  100.7 g                                              wheat starch             7.5 g                                                polyethylene glycol 6000 5.0 g                                                talc                     5.0 g                                                magnesium stearate       1.8 g                                                demineralised water      q.s.                                                 ______________________________________                                    

Preparation

All of the solid ingredients are first of all forced through a sieve of0.6 mm mesh size. The active ingredient, the lactose, the talc, themagnesium stearate and half of the starch are then mixed. The other halfof the starch is suspended in 40 ml of water and this suspension isadded to a boiling solution of the polyethylene glycol in 100 ml ofwater. The resulting starch paste is added to the main mixture which isthen granulated, if necessary with the addition of water. The granulateis dried overnight at 35°, forced through a sieve of 1.2 mm mesh sizeand compressed to form tablets of approximately 6 mm diameter that areconcave on both sides.

EXAMPLE 6

Tablets, each containing 50 mg of the active ingredient, for example(9aR*,9bR*,13aR*)-2,7-dioxo-1,4,5,7,8,9,9a,10,11,12,13,13a-dodecahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole, are prepared as follows:

    ______________________________________                                        Composition (for 10,000 tablets):                                             ______________________________________                                        active ingredient        500.00 g                                             lactose                  140.80 g                                             potato starch            274.70 g                                             stearic acid             10.00 g                                              talc                     50.00 g                                              magnesium stearate       2.50 g                                               colloidal silica         32.00 g                                              ethanol                  q.s.                                                 ______________________________________                                    

A mixture of the active ingredient, the lactose and 194.70 g of potatostarch is moistened with an ethanolic solution of the stearic acid andgranulated through a sieve. After the mixture has been dried, theremainder of the potato starch, the talc, the magnesium stearate and thecolloidal silica are admixed and the mixture is compressed to formtablets each weighing 0.1 g which, if desired, may be provided withdividing notches for finer adjustment of the dose.

100 mg of active ingredient can be employed in an analogous manner.

EXAMPLE 7

Capsules, each containing 0.025 g of the active ingredient, for example(9aR*,9bR*,13aR*)-2,7-dioxo-1,4,5,7,8,9,9a,10,11,12,13,13a-dodecahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole,can be prepared as follows:

    ______________________________________                                        Composition (for 1000 capsules):                                              ______________________________________                                        active ingredient        25.00 g                                              lactose                  249.00 g                                             gelatin                  2.00 g                                               cornstarch               10.00 g                                              talc                     15.0 g                                               water                    q.s.                                                 ______________________________________                                    

The active ingredient is mixed with the lactose, the mixture isuniformly moistened with an aqueous solution of the gelatin andgranulated through a sieve having a mesh size of 1.2 to 1.5 mm. Thegranulate is mixed with the dried cornstarch and the talc and 300 mgportions are introduced into hard gelatin capsules (size 1).

EXAMPLE 8

In an analogous manner to that described in Examples 5 to 7 it is alsopossible to prepare pharmaceutical preparations that contain a differentcompound I or a pharmaceutically acceptable salt of a compound I, forexample according to Examples 1 to 4, as active ingredient.

What is claimed is:
 1. A compound of the formula I ##STR7## in which R₁,R₂, R₃, R₅ and R₇ are each, independent of the others, hydrogen or loweralkyl, m is 2, n is 1, and either R₄ and R₆ are each hydrogen or R₄ andR₆ together form an additional bond, in the free form or in the form ofa salt.
 2. A pharmaceutical preparation comprising a memory improvingeffective amount of a compound according to claim 1 in the free form orin the form of a pharmaceutically acceptable salt thereof in addition toa pharmaceutically acceptable adjunct.
 3. A method of treating a memorydisorder in a subject in need of such treatment, which method comprisesadministering to such subject a memory improving effective amount of acompound according to claim 1 in the free form or in the form of apharmaceutically acceptable salt thereof.
 4. A compound according toclaim 1 of the formula I, in which R₁, R₂, R₃, R₅ and R₇ are each,independently of the others, hydrogen or lower alkyl, m is 2, n is 1,and R₄ and R₆ are each hydrogen, in free form or in form of a salt.
 5. Acompound according to claim 1 of the formula I, in which R₁, R₂, R₃, R₅and R₇ are each hydrogen, m is 2, n is 1, and either R₄ and R₆ are eachhydrogen or R₄ and R₆ together form an additional bond, in free form orin form of a salt.
 6. A compound according to claim 1 of the formula I,in which R₁, R₂, R₃, R₅ and R₇ are each hydrogen, m is 2, n is 1, and R₄and R₆ are each hydrogen, in free form or in form of a salt.
 7. Acompound as claimed in claim 1 being(9aR*,9bR*,13aR*)-2,7-Dioxo-1,4,5,7,8,9,9a,10,11,12,13,13a-dodecahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole.8. A compound as claimed in claim 1 being(9aR*,9bR*,13bR*)-2,7-Dioxo-1,4,5,7,10,11,12,13,13a-decahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole.9. A compound as claimed in claim 1 being the (+)enantiomer of(9aR*,9bR*,13aR*)-2,7-Dioxo-1,4,5,7,8,9,9a,10,11,12,13,13a-dodecahydro-2-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole.10. A compound as claimed in claim 1 being the (-)enantiomer of(9aR*,9bR*,13aR*)-2,7-Dioxo-1,4,5,7,8,9,9a,10,11,12,13,13a-dodecahydro-2-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole.11. A compound as claimed in claim 1 being(9aR*,9bS*,13aS*)-2,7-Dioxo-1,4,5,7,8,9,9a,10,11,12,13,13a-dodecahydro-2H-pyrrolo[[2',1':3,4]pyrazino[2,1-i]indole.